Understanding the role of neurodegenerative disease risk genes in the ageing nervous system

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Though many common neurodegenerative diseases exist in hereditary forms, the vast majority of cases occur sporadically. Human genetic studies have identified many genetic loci and polymorphisms associated with increased risk of developing disorders such as Alzheimer’s disease, however it is frequently unclear how these mutations contribute to pathogenesis. Furthermore it is often the case that the relevant cell type and/or effect upon gene expression accompanying a given genetic association are unclear. Using a combined approach of invertebrate genetics and mammalian cellular model systems we aim to understand how genes associated with increased risk for neurodegenerative diseases contribute to maintenance of the ageing nervous system, focusing on genes linked to sporadic, late-onset Alzheimer’s disease. Using the fruitfly Drosophila melanogaster and powerful invertebrate screening techniques, we aim to understand the effect of cell types specific, altered expression of AD associated genes upon age associated phenotypes, including behaviour, lifespan, neuronal activity, neurodegeneration and autophagosome-lysosome biology. Where appropriate, altered phenotypes and cellular mechanisms identified in our Drosophila screens will be validated in mammalian cell culture system, aiming to identify candidate genes and cellular mechanism for therapeutic intervention.
In addition to our studies of late-onset AD risk genes, we are also utilizing a high-content image analysis approach to understand the contribution of stress on cellular models of amyotrophic lateral sclerosis/frontotemporal dementia. Though ALS and FTD manifest as distinct conditions driven by neurodegeneration in differing regions of the brain, emerging genetic data suggests these disorders exist on a genetic spectrum, with several genes such as C9ORF72 and TBK1 identified in pedigrees where both disorders occur either separately or in combination. The source of this phenotypic heterogeneity within these families is unclear, however is suggestive of genetic or environmental factors modifying pathogenesis. Through use of high-content image analysis we are assessing how different forms of stress (immune, redox, metabolic, etc) induce distinct cellular responses in challenged neurons, and how these are altered by manipulation of genes associated with ALS/FTD. Ultimately we aim to understand how interaction between genetic and environmental factors drive the pathogenesis in these disorders and determine if specific forms of stress result in distinct cellular phenotypes associated with ALS and/or FTD.